Abstract

The METTL3-METTL14 methyltransferase complex adds N6-methyladenosine (m6A) to mRNA with profound impacts on cell fate. Studies delete METTL3 or METTL14 interchangeably to define the role of m6A in target tissues despite a lack of data confirming that these deletions are equivalent. Intestinal epithelial METTL14 deletion triggers stem cell death in the colon with no overt phenotype in the small intestine. The effect of METTL3 deletion in the same tissues remains unknown. We report that intestinal epithelial METTL3 deletion caused unexpected severe defects in the small intestine, including crypt and villus atrophy associated with cellular senescence and death in the crypt transit amplifying zone. Ribosome profiling and m6A-sequencing demonstrated downregulated translation of hundreds of unique methylated transcripts, including genes essential to growth factor signal transduction, such as Kras. Our study suggests that METTL3 is essential for small intestinal homeostasis via enhanced translation of growth factor signaling in crypt transit amplifying cells.